Palbociclib is a cyclin-dependent kinase (CDK4/6) inhibitor developed by Pfizer Inc. It obtained the qualification of “breakthrough therapy” from the U.S. FDA in April 2013. Because of its good clinical performance in Phase III, in August 2014, Pfizer Inc. submitted an application for going on sale to the U.S. FDA and obtained the prioritized examination qualification, and used it for first-line treatment of advanced breast cancer of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−). Successful research of this drug will provide another important choice for the patients with metastatic breast cancer. This drug does not have a standard Chinese translation yet, so the applicant hereby transliterates it as “”.
Chemical name of Palbociclib (I) is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5 -(1-piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one, and its structural formula is:

The synthesis method of Palbociclib was reported in the brand-name drug company's PCT patents such as WO2003062236, WO2008032157, WO2012018540 and WO2012068381 as well as the literature on Pages 2388-2406 in 2005 Vol. 48 in J. Med. Chem. Its preparation mainly includes two synthesis routes.

In Route 1, intermediate A (parent nucleus) and intermediate B (side chain) are taken as the raw materials, and Palbociclib (I) is prepared through the reactions such as substitution reaction, Wittig olefination, acid hydrolysis (rearrangement) and de-protection.

In Route 2, Palbociclib (I) is prepared through the reactions of the changed intermediate A′ (parent nucleus) and intermediate B (side chain) and then through 6-position modification and de-protection.
Through analysis of the above two synthesis routes, the main difference between them is the difference in 2-position substituent groups of intermediates A and A′ (parent nucleus). The intermediate A in Route 1 is 2-halogen (chlorine), and the intermediate A′ in Route 2 is 2-methylsulfinyl group; obviously, the selective difference between 2-methylsulfinyl group and 6-halogen (bromine) in the intermediate A′ is greater than the selective difference between two halogens (chlorine and bromine) in the intermediate A, so the synthesis design in Route 2 avoids a competitive side reaction caused due to two halogens with similar reactivity in Route 1, and greatly improves reaction yield and product purity. However, synthesis of the core intermediates A and A′ (parent nucleus) is relatively complex no matter for Route 1 or Route 2. Its main raw materials 2,5,6-trisubstituted pyrimidine rings are hard to come by, and there are disadvantages such as various reaction steps and complex side reactions, which greatly limits industrial production of this drug.

With regard to the existing process defects, developing an economical and environmentally friendly preparation technology with a simple process and superior quality, especially seeking a process technology which can adapt to industrial production, is of great realistic significance for improvement of economic and social benefits of this drug.